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Placebo: Missverständnisse und Vorurteile
Abstract
Background
The role of placebos is often misunderstood, leading both to overvaluation and to inappropriate disdain. The effect of a placebo that contains no pharmacologically active substance is often confused with the effect of administration by a physician. The aim of this article is to review the current data on placebos, evaluate these data critically, and provide a well-founded and understandable explanation of the effects that placebos do and do not possess.Methods
Selective literature review.ResultsRecent studies employing modern imaging techniques have provided objective correlates of the effect of placebo administration for certain indications. A recent paper even suggested a genetic basis for it. Two main mechanisms underlie the effect of placebo administration: conditioned reflexes, which are subconscious, and the patient's expectations, which are conscious. Further factors include the physician's personality and the setting in which the treatment takes place.Conclusions
The mechanisms of action of placebo administration, with which positive therapeutic effects can be achieved with little effort, should be consciously exploited by physicians when giving their patients pharmacologically active medications as well.
... Der Wirkungsmechanismus eines Placebos wird v. a. auf 2 Mechanismen zurückgeführt: zum einen auf das Phänomen bedingter Reflexe oder Konditionierung und zum anderen auf die Erwartungshaltung des Patienten [5,7,10,21,25]. Während die Erwartungshaltung vorwiegend als bewusster Prozess wahrgenommen wird, ist die Konditionierung eher ein unbewusster Vorgang. Einige Untersuchungen konnten nachweisen, dass die Phänomene Konditionierung und Erwartungshaltung mit neurobiologischen Mechanismen korrespondieren. ...
... Es konnte auch gezeigt werden, dass schon die Kenntnis, an einer placebokontrollierten Studie teilzunehmen, den Placeboeffekt erheblich beeinflussen kann. So erwies sich die Erwartungshaltung trotz der Möglichkeit einer Placebogabe als "robust" [7]. Darüber hinaus ist der Placeboeffekt bei komplexeren Therapieverfahren wie Injektionen oder Akupunktur stärker ausgeprägt als z. ...
Background
The goal of this study was to evaluate the efficacy of laser acupuncture for the clinical picture of chronic back pain under everyday conditions using a randomized, double-blind, placebo-controlled study design. A further aim was to analyze to what extent placebo effects also influence the outcome of acupuncture under these conditions.
Patients and methods
The study included male and female patients with chronic back pain (lasting longer than 6 months) aged between 30 and 77 years with a pain score of at least 5 on a visual analog scale. The main criterion was achieving alleviation of pain by at least 50% 3 months after the start of treatment. The assessment tools used were the Von Korff questionnaire supplemented by the FFbH, FABQ, and SF-12. In addition, the participants were questioned about whether they perceived anything during the treatment and how certain they were that they had received treatment with active or inactive lasers.
Results
A total of 111 patients were included in the study and were treated according to the randomization list in two groups each consisting of 51 subjects. The study was completed as scheduled by 102 participants. Analysis of the primary outcome measure, improvement of the pain score by more than 50% over baseline, revealed improvements in both treatment groups between the time points used for measurement. The placebo group exhibited better levels than the group that received laser treatment. No efficacy advantage of laser acupuncture over placebo treatment could be determined.
Conclusion
It was possible to completely blind the acupuncture forms with the study design employed. Perhaps the consistent exclusion of nonspecific treatment effects contributed to this result. It cannot be ruled out that the effects of acupuncture are based on a strong placebo effect.
... Der Wirkungsmechanismus eines Placebos wird v. a. auf 2 Mechanismen zurückgeführt: zum einen auf das Phänomen bedingter Reflexe oder Konditionierung und zum anderen auf die Erwartungshaltung des Patienten [5,7,10,21,25]. Während die Erwartungshaltung vorwiegend als bewusster Prozess wahrgenommen wird, ist die Konditionierung eher ein unbewusster Vorgang. Einige Untersuchungen konnten nachweisen, dass die Phänomene Konditionierung und Erwartungshaltung mit neurobiologischen Mechanismen korrespondieren. ...
... Es konnte auch gezeigt werden, dass schon die Kenntnis, an einer placebokontrollierten Studie teilzunehmen, den Placeboeffekt erheblich beeinflussen kann. So erwies sich die Erwartungshaltung trotz der Möglichkeit einer Placebogabe als "robust" [7]. Darüber hinaus ist der Placeboeffekt bei komplexeren Therapieverfahren wie Injektionen oder Akupunktur stärker ausgeprägt als z. ...
The goal of this study was to evaluate the efficacy of laser acupuncture for the clinical picture of chronic back pain under everyday conditions using a randomized, double-blind, placebo-controlled study design. A further aim was to analyze to what extent placebo effects also influence the outcome of acupuncture under these conditions.
The study included male and female patients with chronic back pain (lasting longer than 6 months) aged between 30 and 77 years with a pain score of at least 5 on a visual analog scale. The main criterion was achieving alleviation of pain by at least 50% 3 months after the start of treatment. The assessment tools used were the Von Korff questionnaire supplemented by the FFbH, FABQ, and SF-12. In addition, the participants were questioned about whether they perceived anything during the treatment and how certain they were that they had received treatment with active or inactive lasers.
A total of 111 patients were included in the study and were treated according to the randomization list in two groups each consisting of 51 subjects. The study was completed as scheduled by 102 participants. Analysis of the primary outcome measure, improvement of the pain score by more than 50% over baseline, revealed improvements in both treatment groups between the time points used for measurement. The placebo group exhibited better levels than the group that received laser treatment. No efficacy advantage of laser acupuncture over placebo treatment could be determined.
It was possible to completely blind the acupuncture forms with the study design employed. Perhaps the consistent exclusion of nonspecific treatment effects contributed to this result. It cannot be ruled out that the effects of acupuncture are based on a strong placebo effect.
In diagnostic, therapeutic, and nursing contexts, touch is a prerequisite for successful treatment. Compared to other everyday touches, these touches represent exceptional situations in the lives of both patients and the professionals performing the touches.
Social touches can be distinguished from necessary touches that serve a medical or nursing purpose. These social touches, which often occur spontaneously, fulfill social or emotional functions and can have a calming, comforting, or stress-reducing effect. It is possible to use social touches specifically for these effects in medical and nursing contexts.
The chapter informs about emotional, social, and ethical aspects of touch, placebo effects through touch, embodiment effects, effects of pets and animal-assisted therapy, and the effects of loneliness and touch deprivation on health.
Kapitel enthält: emotionale, soziale und ethische Aspekte von Berührungen; Placeboeffekte; Embodiment; Haus- und Therapietiere; Einsamkeit. - Abstract: Im medizinischen Kontext können von erforderlichen Berührungen, die einem medizinischen oder pflegerischen Zweck dienen, soziale Berührungen unterschieden werden. Diese, oft spontan auftretenden Berührungen, erfüllen soziale oder emotionale Funktionen. Soziale Berührungen können beruhigend, tröstend, angst-, schmerz- oder stressreduzierend wirken. Es besteht somit die Möglichkeit, soziale Berührungen im medizinischen oder pflegerischen Kontext gezielt zu diesen Zwecken einzusetzen.
Injection therapies with local anesthetics, analgesics, steroids and other substances for unspecific low back and neck pain are frequently used. Benefits of injections therapies have not been demonstrated satisfactorily; therefore clinical guidelines do not recommend them. Serious adverse events seem to be uncommon but have been reported. Due to insufficient informed consent and the availability of less risky effective alternatives treatment options, injection therapies pose a forensic risk.
Das Spektrum unipolarer depressiver Erkrankungen macht den Hauptteil affektiver Störungen aus und gehört mit einer Inzidenz von ca. 8–20 % zu den häufigsten psychischen Erkrankungen. Ursache und Entstehung sind multifaktoriell bedingt. Neben genetischen Faktoren und biologischer Disposition spielen, je nach Art der depressiven Erkrankung, (persönlichkeits-)psychologische und psychosoziale Faktoren zumindest im Sinne der Auslösung eine Rolle. Aufgrund von klinischen Leitsymptomen, Schweregrad und Verlaufscharakteristika können verschiedene Krankheitsformen, v. a. die depressive Episode, die rezidivierende depressive Störung und die Dysthymie unterschieden werden. Bei rechtzeitiger Diagnose und adäquater Therapie kann die Prognose trotz des häufig rezidivierenden Verlaufs und des Suizidrisikos als gut bezeichnet werden, wenngleich Chronifizierungen und sog. therapieresistente Depressionen in einer Häufigkeit von 15–30 % vorkommen. Therapeutisch stehen die Pharmakotherapie mit Antidepressiva sowie störungsorientierte Psychotherapieverfahren im Vordergrund. Zur Erhaltungs-/Langzeittherapie bzw. Rezidivprophylaxe werden neben Antidepressiva und Stimmungsstabilisierern (kognitive) Verhaltenstherapieverfahren eingesetzt.
Handchirurgen und handchirurgisch tätige Unfallchirurgen, Orthopäden und Plastische Chirurgen sind in der glücklichen Lage, einem »komplexen regionalen Schmerzsyndrom« vorbeugen zu können und im Beginn seine Heilung in die Wege leiten zu können, weil diese Krankheit als Folge von Verletzungen und als Folge von deren Behandlungen an der Hand entstehen kann. Wir wollen erklären, warum und wie.
Als Plazebo (lat.: »ich werde gefallen«) wird eine medizinische Maßnahme, insbesondere ein Arzneimittel, bezeichnet, das durch Fehlen eines spezifischen Agens keine spezifisch wirksamen Effekte haben kann (Gauler u. Weihrauch 1997; Shapiro u. Shapiro 1997; Breidert u. Hofb auer 2009). Gleichwohl entfalten Plazebos erwünschte und unerwünschte Wirkungen und werden auch in psychopharmakologischen Studien zur vergleichenden Untersuchung der Wirksamkeit von wirkstoffhaltigen Präparaten (»Verum«) herangezogen, um den unspezifischen Wirkungsanteil unter vergleichbaren Bedingungen abschätzen zu können. Bei zu erwartenden negativen Wirkungen wird analog von Nozebo (lat.: »ich werde schaden«) gesprochen. Vor Zulassung eines Psychopharmakons zur Behandlung werden in der Regel plazebokontrollierte Studien gefordert (Hippius et al. 1986) (► Kap. 49).
Zusammenfassung Die optimistische Einschätzung, dem Schmerz durch die Allgemeinanästhesie beigekommen zu sein, stammt aus dem 19. Jh. Die
Schmerzbekämpfung jenseits des OP führte jedoch lange Zeit ein Schattendasein. Die Behandlung postoperativer Schmerzen war
unzureichend, die Therapie chronischer Schmerzen vorrangig chirurgisch. Das Extrem stellte die Psychochirurgie dar. In den
Jahren nach dem 2. Weltkrieg etablierte sie sich als eine Methode, mit der versucht wurde, die psychische Verarbeitung der
Schmerzen von ihrem Erleben zu trennen. Der theoretische Ansatz René Leriches, chronische Schmerzen nicht mehr als Symptom,
sondern als Schmerzkrankheit anzusehen, setzte sich bis in die 1950er Jahre nicht durch. Die Grundlagenforschung der Anästhesie,
wie sie Henry Beecher betrieb, trennte die Psyche von der Physiologie in der Betrachtung des pathologischen Schmerzes. Dies
änderte sich durch eine klinische Herangehensweise an die Schmerztherapie, deren Grundlage die Regionalanästhesie war. Die
ersten „pain clinics“ waren „nerve block clinics“. Der Regionalanästhesist John Bonica erweiterte den Rahmen der Schmerztherapie,
indem er die Multidisziplinarität in der Therapie chronischer Schmerzen einforderte. Chronische Schmerzen wurden nach und
nach als eigenständige Krankheit anerkannt und als solche von den Akutschmerzen unterschieden. Sozialwissenschaftliche und
psychologische Ansätze erweiterten die theoretischen Grundlagen der Schmerztherapie. Die Therapie von tumor- und nichttumorbedingten
Schmerzen entwickelte sich unterschiedlich.
I would agree that, when administering pharmacologically effective medications, the mechanisms that underlie the administration of a placebo should be consciously exploited. I would, however, argue that such mechanisms cannot be achieved with very little effort. To influence positively the conditional reflexes and expectations of a patient is not possible without a greater effort being involved—much in the same way as a suitable personal charisma on the doctor’s part and of the atmosphere where the treatment is being given. Doctors are not trained for this, and neither does the medical system expect this of them in everyday clinical practice.
The placebo effect is still being confused with the phenomenon of prescribing a “sham medication.” However, placebo effects as I would describe them are so much more. No surgery, no irradiation treatment, no drug administration, no patient between doctor and patient, no expectation on the doctor’s part or the patient’s part are ever devoid of placebo or nocebo effects, even if this has not been (and probably cannot be) statistically proved in the individual case. These phenomena touch on sociological, philosophical, or even spiritual questions that statistical methods famously cannot capture. Doctors are prone to underestimating the placebo effect and often totally ignore the phenomenon, except when it is essential in drug experiments. Guideline based medicine, which is increasingly based on statistical proof of efficacy, is an obstacle to the access to and inclusion of placebo effects in everyday medical practice.
The authors say in their article that the placebo effect largely depends in a patient’s expectation and contextual factors, such as empathy and attention. The influence of the doctor’s expectations on the result has not been confirmed thus far.
In my opinion, naturopathic remedies meet these requirements in a special manner. On the one hand, patients have great confidence in complementary treatment approaches. Most naturopathic remedies provide much opportunity to deal with patients empathetically because even when taking the history, much emphasis is placed on subjective well-being, and many therapeutic methods entail attentive physical contact between patient and practitioner.
By contrast, patients are often resentful towards scientific orthodox medicine and in particular towards the pharmaceutical industry—as has been shown by the fear of the H1N1 vaccine. Empathy and attention may also be in short supply in medical everyday practice, which is characterized by numerous technical investigations, quality assured documentation, and guideline conform treatment. Among further aggravating factors are discount contracts leading to substitution with cheaper drugs—a cheaper price creates negative expectations, as was mentioned in the article.
I am all the more surprised that the authors in their article declare the placebo effect an important tool in the context of orthodox medical treatment but declare it as questionable in the context of complementary approaches and even class it as “deceiving the patient.” We should end these entrenched wars between complementary medicine and orthodox medicine and should enhance the high technical and scientific standard of our orthodox medical services with the positive placebo characteristics of tried and tested naturopathic treatment methods. With regard to the placebo attributes, these are often superior to orthodox medicine.
The authors explain lucidly how the overall effect after administration of a medical drug is due to specific pharmacological effects on the one hand and to “general effects associated with administration of a placebo or medication” on the other hand. They conclude: “In orthodox medicine, the placebo effect is an important instrument in the physician’s armamentarium.”
Before readers get as far as the summarizing conclusion, however, they may stumble over the sentence: “Placebo effects probably make up a part, if not all, of the effectiveness of alternative and complementary medicine (…) However, since the knowing administration of a placebo for therapeutic purposes means bringing about a false state of affairs that is kept hidden from the patient, it needs to be investigated, as a matter of principle but also as a matter of law, whether purposive administration of placebo does not constitute a deception that must be ethically justified in each individual case (…).”
This statement is akin to demanding that practitioners of complementary medicine should be banned from their profession. What might be behind this undisguised request to dismiss all medical effort outside orthodox medicine as harmful for patients? It cannot be the actual observation of such practitioners and their actual results. It sounds more as though the basis is the claim to be the sole representative of the healing professions that is entailed in our form of medicine, whose intellectual orientation is akin to a “German industry standard,” which aims to eliminate as far as possible all “soft” data—such as the relationship between doctors and patients, which is indescribable and unpredictable —as disruptive elements. Reflecting on the image of doctors and their actions from a generally humane perspective one cannot but conclude that this should include a self critical debate with colleagues about how patients might be given the best possible care.
Placebo effects are ubiquitous in the context of medication therapies. In spite of this fact, they are mostly accepted tacitly within clinical practice. A factual debate of the origin and realization of placebo effects enables their inclusion into orthodox medicine, for the benefit of our patients. In addition to the history and mechanisms of action, one might have wished for the authors to include in their article a practice related listing of medication uses that are particularly susceptible to the influences of the therapeutic environment. Quantitative data are available from meta-analyses of placebo controlled studies. Instead of the otherwise customary difference between pharmacologically active drug (“verum”) and placebo, the relation of the effect sizes of the two treatment arms should be assessed. Such results for 10 typical medication uses in complementary phytotherapy have recently been presented in a journal (1). Under optimal conditions, 60–100% of the effect sizes for the active drug were also achieved under placebo, for symptomatic medication treatments of dysmenorrhea, acute upper respiratory tract infections, anxiety states, symptoms of benign prostatic hyperplasia, irritable bowel symptoms, depression, varicose veins, sleep disorders, pain disorders, and dementias. Statistical data comparisons of this kind are mostly not included in clinical trials, primarily because they would be counterproductive for the purposes of drug licensing. To assess the three influencing variables “pharmacologically related effectiveness,” “innocuousness,” and “cost of treatment” are of major importance for such analyses. The two latter variables gain in importance to the degree that the first variable assumes a marginal importance.
In addition to the above mentioned article, the possibility of genetic and epigenetic signal transduction should be discussed in addition to the historic Pavlovian reflex. Epigenetics is the discipline that researches how gene expression can be influenced from outside the cell. Delayed wound healing, for example, may be caused by psychological stress such as marital conflict, despair, fear, stress, etc (1). So called placebo effects were also found when comparing the results of patients who had had surgery and those who had had sham surgery. The result: no difference was found for debridement versus arthroscopic lavage of the knee versus placebo (2). The fact that some of the “placebo” patients fared better than those who had undergone surgery cannot be conclusively explained. The assumption is that the numerous signal substances that are produced naturally in the body, which are epigenetically influenced by the conscious mind as well as by emotions, may exert a substantial influence on the physiology of the healing process. Placebos are effective in some 35% of cases. In a meta-analysis by the US Food and Drug Administration (FDA), the intrinsic placebo effect for antidepressants is reported to be 80%; in 4 of 47 studies, placebos achieved a better effect than the true, pharmacologically active substance (3). Altogether, the average difference between placebo and medication drugs was not clinically significant. The insights gained into the placebo effect by epigenetic researchers should, as discussed in the article by Breidert and Hofbauer, be cautiously included in the therapeutic concept.
The article only touches on the fact that the so called nocebo effect is known but that barely any research has been conducted to find out more about this effect. In my opinion this constitutes a wide gap in research, because the nocebo effect can occur even if the instructions for use of medications are known and information has been provided—for example, about the risks of surgery. This means that possible side effects of a medication or operation may be caused primarily by the nocebo effect. This presents jurisdiction with difficult situation: on the one hand, it is a legal requirement that patients who have reached the age of consent are fully informed about their treatment. If, however, such nocebo effects develop around the treatment then a legal dilemma arises. It needs to be clarified whether not passing on information about a defined medication weighs more heavily in the balance than a possible nocebo effect. In order to gain an understanding of the frequency of nocebo effects, one might compare, say, the frequency of adverse effects before and after the now legally compulsory information about defined adverse effects was introduced. On the other hand, one might compare the rate of adverse effects associated with a particular treatment in Germany—where a high degree of information about certain adverse effects is a legal requirement—with the rate of adverse effects in countries where German physicians work but where the legal requirement for information about medical therapies is less stringent. The United Arab Emirates is one such example.
Placebokontrollierte Studien sind heutzutage der „Goldstandard“ für die „evidenzbasierte Medizin“ in der Untersuchung klinischer
Fragestellungen wie der Schmerztherapie. Dabei steht der Placeboeffekt nicht im eigentlichen Fokus des Interesses, sondern
dient lediglich als Kontrolle für die Spezifität des Effektes einer bestimmten Behandlung. Was Mediziner häufig nicht erkennen,
ist, dass der Placeboeffekt ein echtes, messbares Korrelat einer psychoneurobiologischen Reaktion des Organismus darstellt
und damit selbst Einfluss auf den Heilungsprozess, wie z.B. die Schmerzlinderung, nehmen kann. Placebo ist also nicht gleichbedeutend
mit „keine Therapie“. Placeboresponder, Ausmaß und Dauer des Placeboeffektes stellen keinen fixen Anteil dar, sondern unterliegen
deutlich größerer Variabilität als bisher angenommen. Der Mythos, dass Placeboresponder eine bestimmte Persönlichkeit haben,
hat sich nicht bestätigt, jedoch können das Arzt-Patient-Verhältnis und soziokulturelle Faktoren einen entscheidenden Einfluss
auf den Placeboeffekt nehmen. Psychologische Erklärungsansätze zeigen, dass die klassische Konditionierung, die gesteigerte
Erwartungshaltung und die Motivation des Patienten das Ausmaß des Placeboeffektes bestimmen. Diese wiederum können Einfluss
auf neurobiologische Systeme nehmen, wie z.B. das endogene Opioidsystem, das entsprechend den modernen bildgebenden Verfahren
v.a. in schmerzrelevanten Arealen aktiviert wird und zum Effekt der Placeboanalgesie beiträgt. Placeboeffekte, die in kontrollierten
klinischen Studien bewusst vermieden werden sollen, können in der klinischen Praxis zur Optimierung des Gesamttherapieeffektes
erwünscht sein. Dies sollte die Maximierung des situativen Kontexteffektes jeder therapeutischen Intervention zur Steigerung
des Gesamttherapieeffektes – wie es in den neuesten Leitlinien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen
Fachgesellschaften (AWMF) zur postoperativen Schmerztherapie empfohlen wird –, jedoch nicht die beabsichtigte isolierte Gabe
einer inerten Substanz bedeuten. Letzteres ist rigorosen ethischen Richtlinien unterworfen und nur nach vorheriger Begutachtung
durch die Ethikkommission im Rahmen von kontrollierten klinischen Studien möglich. Eine denkbare Alternative mag der von Benedetti
vorgeschlagene Weg sein, bei dem die versteckte Gabe eines Verums den spezifischen Effekt identifiziert, im Gegensatz zur
angekündigten Gabe desselben Verums, das den spezifischen und den Placeboeffekt charakterisiert, woraus man letztendlich das
Ausmaß des Placeboeffektes bestimmen kann.
Placebo controlled studies examining clinical problems, e.g. in pain therapy, are considered the „gold standard“ for evidence-based
medicine. In these studies the placebo effect itself is not the main focus of interest, but serves more as a control for the
specificity of the effect of a certain treatment. What physicans in this context often do not realize is that the placebo
effect itself represents a true measurable correlate of an organism’s psycho-neurobiological response and, thereby, influences
the healing process, e.g. the pain relief. Placebo is, therefore, not equivalent to „no treatment“. The number of placebo
responders, the degree and the duration of the placebo effect is not fixed, but are subject to a much greater variability
then hitherto believed. The myth that placebo responders have a certain personality has not been proven correct; instead,
the relationships between physicians and patients as well as sociocultural factors have a considerable impact on the placebo
effect. Psychological theories explain that classical conditioning, enhanced expectation and motivation of the patient determine
the degree of the placebo effect. These directly influence neurobiological systems such as the endogenous opioids which according
to modern brain imaging are predominantly activated in pain-relevant areas and contribute to the effect of placebo analgesia.
Placebo effects that should be deliberately excluded in controlled clinical trials, can be desirable in clinical practice
to optimize the total therapeutic effect. This should mean that the context effect of each therapeutic intervention is maximized
towards an improved therapeutic effect, as outlined in the recent AWMF guidelines for postoperative pain therapy, but should
not include the administration of an inert substance. The latter is controlled by rigorous ethical guidelines and is only
permitted in the context of ethically approved controlled clinical trials. A possible alternative is suggested by Benedetti
et al. in which the hidden administration of an active substance identifies the specific response in contrast to the open
application of the same substance characterizing the specific plus the placebo effect, after which the pure placebo effect
can be determined.
Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.
Background
Placebo treatments have been reported to help patients with many diseases, but the quality of the evidence supporting this finding has not been rigorously evaluated.
Methods
We conducted a systematic review of clinical trials in which patients were randomly assigned to either placebo or no treatment. A placebo could be pharmacologic (e.g., a tablet), physical (e.g., a manipulation), or psychological (e.g., a conversation).
Results
We identified 130 trials that met our inclusion criteria. After the exclusion of 16 trials without relevant data on outcomes, there were 32 with binary outcomes (involving 3795 patients, with a median of 51 patients per trial) and 82 with continuous outcomes (involving 4730 patients, with a median of 27 patients per trial). As compared with no treatment, placebo had no significant effect on binary outcomes, regardless of whether these outcomes were subjective or objective. For the trials with continuous outcomes, placebo had a beneficial effect, but the effect decreased with increasing sample size, indicating a possible bias related to the effects of small trials. The pooled standardized mean difference was significant for the trials with subjective outcomes but not for those with objective outcomes. In 27 trials involving the treatment of pain, placebo had a beneficial effect, as indicated by a reduction in the intensity of pain of 6.5 mm on a 100-mm visual-analogue scale.
Conclusions
We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos.
Prospective study with patient and physician questionnaires, clinical records, and imaging.
To compare physician expectations of surgery for sciatica and patient outcome.
Physician accuracy in identifying individual patient prognosis is important for therapeutic decisions.
A total of 197 consecutive patients with low back pain and/or sciatica who underwent low back surgery in the University Hospital of Lausanne, Switzerland.
Physicians predicted "a great improvement" of quality of life after surgery for 79% and "moderate improvement" for 20% (1% others); 39% of patients had no "minimal clinically important difference" in back pain after surgery, despite physician prediction of "great improvement." Correlations between physician expectation and various dimensions of patient outcome were not significant, and agreement with patient global judgment of 1-year outcome was poor (kappa = 0.03). However, in a subgroup where the indication for treatment was not considered appropriate, physician prediction of "great improvement" was followed by greater improvement outcome on SF-36 mental component score (P = 0.05), mental health (0.02), and general health (0.03) compared with patients where the physician did not predict "great improvement."
Despite clear average improvement, surgeons tended to give overly optimistic predictions that were not correlated with patient outcome. For patients receiving a treatment not meeting explicit criteria of appropriateness, more optimistic physician expectation was associated with better improvement of psychological dimensions. Besides prognostic ability, the influence of physician expectation on patient outcome is discussed and the concept of "curabo effect" (differentiated from "placebo effect") proposed.
Despite the increasing research on placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of symptom worsening play a crucial role. By studying experimental ischemic arm pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of adrenocorticotropic hormone and cortisol plasma concentrations. Both nocebo hyperalgesia and HPA hyperactivity were antagonized by the benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed cholecystokinin (CCK) type-A/B receptor antagonist proglumide blocked nocebo hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both diazepam and proglumide did not show analgesic properties on basal pain, because they acted only on the nocebo-induced pain increase. These data indicate a close relationship between anxiety and nocebo hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced hyperalgesia. These results, together with previous findings showing that placebo analgesia is mediated by endogenous opioids, suggest that the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.
Despite the importance and pervasiveness of marketing, almost nothing is known about the neural mechanisms through which it affects decisions made by individuals. We propose that marketing actions, such as changes in the price of a product, can affect neural representations of experienced pleasantness. We tested this hypothesis by scanning human subjects using functional MRI while they tasted wines that, contrary to reality, they believed to be different and sold at different prices. Our results show that increasing the price of a wine increases subjective reports of flavor pleasantness as well as blood-oxygen-level-dependent activity in medial orbitofrontal cortex, an area that is widely thought to encode for experienced pleasantness during experiential tasks. The paper provides evidence for the ability of marketing actions to modulate neural correlates of experienced pleasantness and for the mechanisms through which the effect operates.
• orbitofrontal cortex
• modulation by marketing actions
• neuroeconomics
• taste
To investigate whether placebo effects can experimentally be separated into the response to three components-assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship-and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components.
A six week single blind three arm randomised controlled trial.
Academic medical centre.
262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of > or =150 on the symptom severity scale.
For three weeks either waiting list (observation), placebo acupuncture alone ("limited"), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence ("augmented"). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks.
Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life.
At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus "limited" versus "augmented," respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01). Results were similar at six week follow-up.
Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component.
Clinical Trials NCT00065403.
Study Design. Prospective study with patient and physician questionnaires, clinical records, and imaging. Objective. To compare physician expectations of surgery for sciatica and patient outcome. Summary of Background Data. Physician accuracy in identifying individual patient prognosis is important for therapeutic decisions. Methods. A total of 197 consecutive patients with low back pain and/or sciatica who underwent low back surgery in the University Hospital of Lausanne, Switzerland. Results. Physicians predicted "a great improvement" of quality of life after surgery for 79% and "moderate improvement" for 20% (1% others); 39% of patients had no "minimal clinically important difference" in back pain after surgery, despite physician prediction of "great improvement." Correlations between physician expectation and various dimensions of patient outcome were not significant, and agreement with patient global judgment of 1-year outcome was poor (kappa = 0.03). However, in a subgroup where the indication for treatment was not considered appropriate, physician prediction of "great improvement" was followed by greater improvement outcome on SF-36 mental component score (P = 0.05), mental health (0.02), and general health ( 0.03) compared with patients where the physician did not predict "great improvement." Conclusion. Despite clear average improvement, surgeons tended to give overly optimistic predictions that were not correlated with patient outcome. For patients receiving a treatment not meeting explicit criteria of appropriateness, more optimistic physician expectation was associated with better improvement of psychological dimensions. Besides prognostic ability, the influence of physician expectation on patient outcome is discussed and the concept of "curabo effect" ( differentiated from "placebo effect") proposed.
Abstract
Regression to the mean
The evaluation of rehabilitation programs may be distorted by regression to the mean: In a group of patients with extreme measurement values, these values tend to be less extreme on a following point in time due to merely random components and regardless of a ‘true’ treatment effect. If this effect is not taken into account, the effectiveness of rehabilitation programs may be estimated wrongly. In this paper regression to the mean is explained comprehensively and common misunderstandings are clarified. It is shown, which conditions are crucial for regression to the mean to arise and which factors determine its strength. Furthermore it is shown how regression to the mean should be controlled in repeated measurement designs.
Placebos have doubtless been used for centuries by wise physicians as well as by quacks, but it is only recently that recognition of an enquiring kind has been given the clinical circumstance where the use of this tool is essential "... to distinguish pharmacological effects from the effects of suggestion, and... to obtain an unbiased assessment of the result of experiment." It is interesting that Pepper could say as recently as 10 years ago "apparently there has never been a paper published discussing [primarily] the important subject of the placebo." In 1953 Gaddum1 said:
Such tablets are sometimes called placebos, but it is better to call them dummies. According to the Shorter Oxford Dictionary the word placebo has been used since 1811 to mean a medicine given more to please than to benefit the patient. Dummy tablets are not particularly noted for the pleasure which they give to their recipients.
In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.
To assess the impact of the colour of a drug's formulation on its perceived effect and its effectiveness and to examine whether antidepressant drugs available in the Netherlands are different in colour from hypnotic, sedative, and anxiolytic drugs.
Systematic review of 12 published studies. Six studies examined the perceived action of different coloured drugs and six the influence of the colour of a drug on its effectiveness. The colours of samples of 49 drugs affecting the central nervous system were assessed using a colour atlas.
Perceived stimulant action versus perceived depressant action of colour of drugs; the trials that assessed the effect of drugs in different colours were done in patients with different diseases and had different outcome measures.
The studies on perceived action of coloured drugs showed that red, yellow, and orange are associated with a stimulant effect, while blue and green are related to a tranquillising effect. The trials that assessed the impact of the colour of drugs on their effectiveness showed inconsistent differences between colours. The quality of the methods of these trials was variable. Hypnotic, sedative, and anxiolytic drugs were more likely than antidepressants to be green, blue, or purple.
Colours affect the perceived action of a drug and seem to influence the effectiveness of a drug. Moreover, a relation exists between the colouring of drugs that affect the central nervous system and the indications for which they are used. Research contributing to a better understanding of the effect of the colour of drugs is warranted.
In 1955, Henry K. Beecher published the classic work entitled "The Powerful Placebo." Since that time, 40 years ago, the placebo effect has been considered a scientific fact. Beecher was the first scientist to quantify the placebo effect. He claimed that in 15 trials with different diseases, 35% of 1082 patients were satisfactorily relieved by a placebo alone. This publication is still the most frequently cited placebo reference. Recently Beecher's article was reanalyzed with surprising results: In contrast to his claim, no evidence was found of any placebo effect in any of the studies cited by him. There were many other factors that could account for the reported improvements in patients in these trials, but most likely there was no placebo effect whatsoever. False impressions of placebo effects can be produced in various ways. Spontaneous improvement, fluctuation of symptoms, regression to the mean, additional treatment, conditional switching of placebo treatment, scaling bias, irrelevant response variables, answers of politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgment, psychosomatic phenomena, misquotation, etc. These factors are still prevalent in modern placebo literature. The placebo topic seems to invite sloppy methodological thinking. Therefore awareness of Beecher's mistakes and misinterpretations is essential for an appropriate interpretation of current placebo literature.
This article examines the role of placebos in evaluating the efficacy of psychiatric drugs. Also addressed are the identification of placebo effects on drugs, the relevance of active placebo, the need for placebo groups in psychotherapy studies, and ethical issues concerning the use of placebo.
Psychiatric drug treatment trials were reviewed. Emphasis was placed on studies with ambiguous outcomes, studies using an active placebo, and studies attempting to understand the role of placebo effects on patients receiving a drug. The concept of pattern analysis for identifying true drug effect is reviewed.
Evidence that placebos are required to prevent a false conclusion about drug efficacy is presented. The public health implications of concluding that an ineffective drug is beneficial are examined. Active placebos do not appear necessary, and there is some evidence that the odds of identifying a patient who has improved as a result of true drug effect (as opposed to placebo effect) exceed chance with pattern analysis.
Psychiatric disorders have a fluctuating course, psychiatry's phenomenologically based nosological system is inexact, and the interaction between these two leads to a large proportion of patients experiencing a placebo effect. It may be possible to identify patients receiving an antidepressant who improved as a result of a placebo effect. This is an educated guess that may be helpful in planning the treatment of patients who have a contraindication to continuing a psychopharmacological regimen.
Throughout history, doctor-patient relationships have been acknowledged as having an important therapeutic effect, irrespective of any prescribed drug or treatment. We did a systematic review to determine whether there was any empirical evidence to support this theory.
A comprehensive search strategy was developed to include 11 medical, psychological, and sociological electronic databases. The quality of eligible trials was objectively assessed by two reviewers, and the type of non-treatment care given in each trial was categorised as cognitive or emotional. Cognitive care aims to influence patients' expectations about the illness or the treatment, whereas emotional care refers to the style of the consultation (eg, warm, empathic), and aims to reduce negative feelings such as anxiety and fear.
We identified 25 eligible randomised controlled trials. 19 examined the effects of influencing patients' expectations about treatment, half of which found significant effects. None of the studies examined the effects of emotional care alone, but four trials assessed a combination of both cognitive and emotional care. Three of these studies showed that enhancing patients' expectations through positive information about the treatment or the illness, while providing support or reassurance, significantly influenced health outcomes.
There is much inconsistency regarding emotional and cognitive care, although one relatively consistent finding is that physicians who adopt a warm, friendly, and reassuring manner are more effective than those who keep consultations formal and do not offer reassurance.
Patients taking active medications frequently experience adverse, nonspecific side effects that are not a direct result of the specific pharmacological action of the drug. Although this phenomenon is common, distressing, and costly, it is rarely studied and poorly understood. The nocebo phenomenon, in which placebos produce adverse side effects, offers some insight into nonspecific side effect reporting. We performed a focused review of the literature, which identified several factors that appear to be associated with the nocebo phenomenon and/or reporting of nonspecific side effects while taking active medication: the patient's expectations of adverse effects at the outset of treatment; a process of conditioning in which the patient learns from prior experiences to associate medication-taking with somatic symptoms; certain psychological characteristics such as anxiety, depression, and the tendency to somatize; and situational and contextual factors. Physicians and other health care personnel can attempt to ameliorate nonspecific side effects to active medications by identifying in advance those patients most at risk for developing them and by using a collaborative relationship with the patient to explain and help the patient to understand and tolerate these bothersome but nonharmful symptoms.
It is widely believed that placebo interventions induce powerful effects. We could not confirm this in a systematic review of 114 randomized trials that compared placebo-treated with untreated patients.
To study whether a new sample of trials would reproduce our earlier findings, and to update the review.
Systematic review of trials that were published since our last search (or not previously identified), and of all available trials.
Data was available in 42 out of 52 new trials (3212 patients). The results were similar to our previous findings. The updated review summarizes data from 156 trials (11 737 patients). We found no statistically significant pooled effect in 38 trials with binary outcomes, relative risk 0.95 (95% confidence interval 0.89-1.01). The effect on continuous outcomes decreased with increasing sample size, and there was considerable variation in effect also between large trials; the effect estimates should therefore be interpreted cautiously. If this bias is disregarded, the pooled standardized mean difference in 118 trials with continuous outcomes was -0.24 (-0.31 to -0.17). For trials with patient-reported outcomes the effect was -0.30 (-0.38 to -0.21), but only -0.10 (-0.20 to 0.01) for trials with observer-reported outcomes. Of 10 clinical conditions investigated in three trials or more, placebo had a statistically significant pooled effect only on pain or phobia on continuous scales.
We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient-reported continuous outcomes, especially pain, could not be clearly distinguished from bias.
Placebo, used here to mean an inert treatment given as if it was a real treatment, means lots of different things to different people. The structure of the article is that it begins by talking about the technical use of placebos in clinical trials, and the extent of the placebo response, then about the mechanism--"How does the placebo work?"--and last about the ethics of placebo in the contexts of research and in everyday practice.
Prior investigations have failed to find reliable personality differences in placebo responding. The present study tests the hypothesis that personality and situational variables interact to determine placebo responding.
Optimists and pessimists were randomly assigned to one of three conditions. In the first condition, the participants were told that they were to ingest a pill that would make them feel unpleasant (deceptive-expectation group). In the second condition, the participants were told that they were to ingest a pill that would make them feel either unpleasant or was an inactive substance (conditional-expectation group). Finally, a third group was told they were to ingest a pill that was inactive (control group).
Pessimists were more likely than optimists to follow a negative-placebo expectation when given a deceptive expectation, but not when given a conditional expectation.
The personality variable optimism-pessimism relates to placebo responding when individuals are given a deceptive but not a conditional expectation. This suggests that personality and situational variables interact to determine placebo responding.
Because of the recent and controversial example of sham surgery for the evaluation of fetal tissue transplants for Parkinson's disease, there is renewed interest in the ethics of using "active" placebos in surgical trials, where otherwise there are no inert procedures available, and in pharmacological trials, where there are inert substances, but where patients may guess to which arm they have been allocated. This paper seeks to clarify the ethical arguments surrounding the use of active placebos in trials, and to set up a notation for assessing the ethics of trials more generally. We first establish an framework by which ethics committees can analyze such trials. We examine (1) the scientific value of the research; (2) the expected risks and benefits to individual patients, and (3) the voluntary nature of consent. We then contrast the implications of this framework for inert and active placebo-controlled trials, respectively. In particular, we analyze their relative expected utility using three main utility factors, namely, treatment effects, placebo effects, and altruism. We conclude that, when the intervention is already widely available, active placebo trials rely more heavily on altruism than do inert placebo trials and, when the intervention is restricted, this excess reliance may not be needed. What our analysis provides is the explicit justification for the apparent caution of Institutional Review Boards or ethics committees when reviewing sham operations, especially when the expected harm is not trivial and the risk of exploitation is high.
Homoeopathy is widely used, but specific effects of homoeopathic remedies seem implausible. Bias in the conduct and reporting of trials is a possible explanation for positive findings of trials of both homoeopathy and conventional medicine. We analysed trials of homoeopathy and conventional medicine and estimated treatment effects in trials least likely to be affected by bias.
Placebo-controlled trials of homoeopathy were identified by a comprehensive literature search, which covered 19 electronic databases, reference lists of relevant papers, and contacts with experts. Trials in conventional medicine matched to homoeopathy trials for disorder and type of outcome were randomly selected from the Cochrane Controlled Trials Register (issue 1, 2003). Data were extracted in duplicate and outcomes coded so that odds ratios below 1 indicated benefit. Trials described as double-blind, with adequate randomisation, were assumed to be of higher methodological quality. Bias effects were examined in funnel plots and meta-regression models.
110 homoeopathy trials and 110 matched conventional-medicine trials were analysed. The median study size was 65 participants (range ten to 1573). 21 homoeopathy trials (19%) and nine (8%) conventional-medicine trials were of higher quality. In both groups, smaller trials and those of lower quality showed more beneficial treatment effects than larger and higher-quality trials. When the analysis was restricted to large trials of higher quality, the odds ratio was 0.88 (95% CI 0.65-1.19) for homoeopathy (eight trials) and 0.58 (0.39-0.85) for conventional medicine (six trials).
Biases are present in placebo-controlled trials of both homoeopathy and conventional medicine. When account was taken for these biases in the analysis, there was weak evidence for a specific effect of homoeopathic remedies, but strong evidence for specific effects of conventional interventions. This finding is compatible with the notion that the clinical effects of homoeopathy are placebo effects.
The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.
To examine the placebo effect and its potential determinants in the treatment of osteoarthritis (OA) via a systematic literature search of Medline, EMBASE, Scientific Citation Index, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library.
Randomised placebo controlled trials in OA were included. The placebo effect was defined as the overall change from baseline in the placebo group. It was estimated as the effect size (ES; the standard mean difference between baseline and endpoint) and this was compared with the ES obtained from untreated control. ES for pain was the primary outcome. Statistical pooling was undertaken as appropriate and 95% CIs were used for comparison. Quality of trials was assessed and potential determinants of placebo effect were examined using multiple regression analysis. The partial regression coefficient (beta) was used to present the adjusted size of the association.
We identified 198 trials with 193 placebo groups (16 364 patients) and 14 untreated control groups (1167 patients) that met our inclusion criteria. These included a range of therapies (non-pharmacological, pharmacological and surgical treatments). Placebo was effective at relieving pain (ES 0.51, 95% CI 0.46 to 0.55 for the placebo group and 0.03, 95% CI -0.13 to 0.18 for untreated control). Placebo was also effective at improving function and stiffness. The pain-relieving effect increased when the active treatment effect (beta=0.38, p<0.001), baseline pain (0.006, p=0.014) and sample size (0.001, p=0.004) increased, and when placebo was given through injections/needles (0.144, p=0.020).
Placebo is effective in the treatment of OA, especially for pain, stiffness and self-reported function. The size of this effect is influenced by the strength of the active treatment, the baseline disease severity, the route of delivery and the sample size of the study.
Is the placebo powerless?
- A Hrobjartsson
- Gotzsche
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Hrobjartsson A, Gotzsche PC: Is the placebo powerless? N Engl J Med 2001; 344: 1594–602
Th e powerful placebo
- Beecher
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Beecher HK: Th e powerful placebo. JAMA 1955; 159: 1602–6.
Th e nocebo reaction
- Kennedy
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Kennedy WP: Th e nocebo reaction. Med World 1961; 95: 203–5.